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Molecular organization and pharmacological properties of the voltage-gated sodium channel signaling complex
Voltage-activated sodium (Nav) channels are found throughout the human body where they form the cornerstones of fast electrical signaling by regulating the Na+ permeability of the cell membrane. As such, Nav channels are among the most widely targeted ion channels by both drugs and animal toxins. Their medical relevance is underscored by mutations that underlie debilitating disorders such as epilepsy, muscle weakness, cardiac arrhythmias and pain syndromes. Despite their physiological importance, our understanding of these channels is hampered by a lack of insight into their complex structures and working mechanisms. Rather than existing as independent units, Nav channels are part of a signaling complex that involves auxiliary proteins and membrane lipids. Our goal is to address fundamental questions on the identities of the Nav channel signaling complex components and to resolve their mechanisms of action at the molecular level. To this end, we combine several techniques including molecular biology, electrophysiology, genetics, and biochemistry. Successful completion of these goals will reveal key elements in the Nav channel signaling complex, help define Nav channel function in normal and pathological states, and may offer novel strategies for developing therapeutic drugs.
Klint, J.K., Smith, J.J., Vetter, I., Rupasinghe, D.B., Er, S.Y., Senff, S., Herzig, V., Mobli, M., Lewis, R.J., Bosmans, F.*, King, G.F*. (*Co-corresponding authors) Seven novel modulators of the analgesic target NaV1.7 uncovered using a high-throughput venom-based discovery approach. (2015)British Journal of Pharmacology, 172 (10): 2445-2458. PMCID: PMC4409898.
Ahern, C.A.*, Payendeh, J.*, Bosmans, F.*, Chanda, B* (*Co-corresponding authors). A hitchhiker’s guide to the sodium channel galaxy. (2015)Journal of General Physiology, 147 (1): 1-24. PMCID:PMC4692491.
Das, S., Gilchrist, J.,Bosmans, F.*, Van Petegem, F.* (*Co-corresponding authors). Binary architecture of the Nav1.2/?2 signaling complex.eLife, in press.
Rosso JP, Schwartz JR, Diaz-Bustamante M, Ceard B, Gutierrez JM, Kneussel M, Pongs O, Bosmans F, Bougis PE. MmTX1 and MmTX2 from coral snake venom potently modulate GABAA receptor activity. Proc Natl Acad Sci USA, 2015 Feb 24; 112(8):E891-900. doi: 10.1073/pnas. 1415488112. Epub 2015 Feb 9.
Martin-Eauclaire MF, Ferracci G, Bosmans F, Bougis PE. A surface plasmon resonance approach to monitor toxin interactions with an isolated voltge-gated sodium channel paddle motif. J Gen Physiol. 2015 Feb; 145(2): 155-62. doi: 1085/jgp.201411268.
Kalia J, Milescu M, Salvatierra J, Wagner J, Klint JK, King GF, Olivera BM, Bosmans F. From foe to friend: Using animal toxins to investigate ion channel function. J Mol Biol. 2014 PubMed Reference Bende NS, Dziemborowicz S, Mobli M, Herzig V, Gilchrist J, Wagner J, Nicholson GM, King GF, Bosmans F. A distinct sodium channel voltage-sensor locus determines insect selectivity of the spider toxin Dc1a. Nat Commun. 2014
Gilchrist J, Olivera BM, Bosmans F. Animal toxins influence voltage-gated sodium channel function. Handb Exp Pharmacol. 2014
Gilchrist J, Dutton S, Diaz-Bustamante M, McPherson A, Olivares N, Kalia J, Escayg A, Bosmans F. Nav1.1 modulation by a novel triazole compound attenuates epileptic seizures in rodents. ACS Chem Biol. 2014
Gilchrist J, Das S, Van Petegemb F, and Bosmans F a,d,2. Crystallographic insights into sodium-channel odulation by the ?4 subunit. PNAS 10(1073): 1314557110, July 2013.
Bosmans F. New rule(r)s for FRET. Biophys J. 2013
Bosmans F and Gilchrist J. Animal Toxins Can Alter the Function of Nav1.8 and Nav1.9. Toxins 2012. 4, 620-632; doi:10.3390/toxins4080620.
Bosmans F, Puopolo M, Martin-Eauclaire M-F, Bean BP and Swartz KJ. Functional properties and toxin pharmacology of a dorsal root ganglion sodium channel viewed through its voltage sensors. PubMed Reference Journal of General Physiology 138(1):59-72, 2011.
Bosmans F, Milescu M and Swartz KJ. Palmitoylation influences the function and pharmacology of sodium channels. PNAS 108(50): 20213-20218, 2011.
Bosmans F and Swartz KJ. Targeting voltage sensors in sodium channels with spider toxins. Trends in Pharmacological Sciences 31(4) 175:182, 2010.
Milescu M, Bosmans F, Lee S, Alabi AA, Swartz JIK and JK. Interactions between lipids and voltage sensor paddles detected with tarantula toxins. Nature Structural & Molecular Biology 16(10):1080-1086, October 2009.
Bosmans F, Martin-Eauclaire M-F and Swartz KJ. Deconstructing voltage sensor function and pharmacology in sodium channels. Nature 456(7219):202-208 November 13, 2008.